This invention relates to 2-substituted thiazolidinone derivatives which are xcex23 adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination, and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of xcex2 adrenergic receptors (xcex2-AR) into xcex21- and xcex22-AR has led to the development of xcex21- and xcex22-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of xe2x80x9catypicalxe2x80x9d receptors, later called xcex23-AR, has led to the development of xcex23-AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on xcex23-AR agnoists, see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.
Compounds that are potent and selective xcex23 agonists, may be potentially useful antiobesity agents. Low levels or lack of xcex21 and xcex22 agonistic properties will minimize or eliminate the adverse side effects that are associated with xcex21 and xcex22 agonistic activities, i.e. increased heart rate, and muscle tremor, respectively.
Early developments in the xcex23-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, 5,153,210. Although the early developments purport to claim compounds with greater xcex23-AR selectivity over the xcex21- and xcex22-AR. However, clinical trials in humans with those early developed xcex23-agonists have, so far, not been successful.
More recently, potent and selective human xcex23 agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures, expressing cloned human xcex23 receptors, which predict the effects that can be expected in humans (Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).
xcex23-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J H, Yasay G D and Kau S T Pharmacology 1992; 44: 13-18). Beta-adrenoceptor subtypes are in the detrusor of guinea-pig urinary bladder. Recently, a number of laboratories have provided experimental evidence of xcex23 adrenergic receptors in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Br. J. Pharmacol. 1998; 124: 593-599), and that activation of the xcex23 receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder.
Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized my abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, xcex23 adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled xcex23 receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the xcex23 adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, xcex23 adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective xcex23 adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
This invention provides compounds of Formula I having the structure 
wherein:
A is aryl or Het;
X is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or a bond;
Y is alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, azetidine, pyrrolidine or piperidine; wherein the nitrogen of the azetidine, pyrrolidine or piperidine attached to the adjacent phenyl ring;
Z is S, O, NH or N-alkyl of 1-6 carbon atoms;
R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino, or two of the three substituents (R1, R2 and R3) combine with the carbon to which each is attached to form a aryl fused cycloalkyl of 3-8 carbon atoms optionally substituted with acylamino or hydroxy;
R4 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, carboxy, or halogen;
R5 is hydrogen or alkyl of 1-6 carbon atoms;
R6 is (i) SCH3 or NR7R8; (ii) an amino acid, wherein the nitrogen of amino acid is attached to the adjacent thiazolidinone, oxazolidinone, or imidazolidinone ring; (iii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid is attached to the adjacent thiazolidinone, oxazolidinone, or imidazolidinone ring, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; or (iv) NH(C=Q)NR7R8 or NHNH(C=Q)NR7R8;
R7 and R8 are each, independently, hydrogen, aryl, Het, alkyl of 1-6 carbon atoms, arylalkyl in which the alkyl moiety has 1-6 carbon atoms, Hetalkyl in which the alkyl moiety has 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, hydroxy, alkoxy of 1-6 carbon atoms, benzyloxy, cyano, alkylamino of 1-6 carbon atoms, dialkylamino having 1-6 carbon atoms per alkyl group, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms; or R7 and R8 are taken together with the nitrogen to which each is attached to form a saturated, unsaturated, or partially unsaturated 3-8 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from S, O and N, and optionally substituted with R9;
Q is O, S, NH, NCN; or Q and one of R7 and R8 are taken together to form a partially unsaturated or unsaturated 3-8 membered heterocyclic ring optionally containing 1-2 additional heteroatoms selected from S, O, and N, and optionally substituted with R9;
Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the heterocycle may be saturated, unsaturated, or partially unsaturated; may be optionally fused to a phenyl ring, and may be optionally substituted with R9;
R9 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl group, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human xcex23 adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium), alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
Alkyl includes both straight chain as well as branched moieties. By definition alkyl also includes alkyl moieties which are optionally mono- or poly substituted with groups such as halogen, hydroxy, cyano, alkoxy, aryloxy, arylalkyl, alkylthio, arylthio, amino, alkylamino, and dialkylamino. Halogen means bromine, chlorine, fluorine, and iodine. Where a substituent contains one or more moieties which have the same designation, each of the moieties can be the same or different.
Preferred aryl moieties include phenyl or naphthyl. Preferred Het moieties include: (a) 6-membered saturated, partially unsaturated, or unsaturated heterocycles containing 1-2 nitrogens, optionally fused to a phenyl ring; (b) 5-membered saturated, partially saturated, or unsaturated heterocycles containing 1-3 nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl ring; (c) saturated, partially unsaturated, or unsaturated bicyclic heterocycles containing 1-4 nitrogen, oxygen, or sulfur atoms; (d) carbazole, dibenzofuran, and dibenzothiophene. In the Het of categories (a), (b), and (c), ring carbon atoms may be carbonyl moieties, where the ring does not contain a double bond in that position (for example, thiazolidine-2,4-dione).
More preferred Het rings include pyrrole, furan, thiophene, imidazole, pyrazole, furazan, triazole, tetrazole, oxazoel, oxadiazole, isoxazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5-triazine, 1,2,4,5-tetrazine, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazol, 3H-benzoxazol-2-one, benzotriazole, quinoline, isoquinoline, quinazoline, indazole, 1H-quinolin-2-one, 3,4-dihydro-1H-quinolin-2-one, 2,3-dihydro-1H-indole, 1,3-dihydro-benzoinimidazol-2-one, 1,3-dihydro-benzoinimidazol-2-thione, and carbazole. It is understood that Het do not contain heteroatoms in arrangements which would make them inherently unstable. For example, the term Het does not include ring systems containing Oxe2x80x94O bonds in the ring backbone.
Preferred amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, xcex2-alanine, cyclopropane amino acids (such as 1-aminocyclopropane-1-carboxylic acid, allo-coronamic acid and 2,3-methanohomoserine), 1 -aminocyclohexane-1-carboxylic acid, isonipecotic acid, 2-azetidinecarboxylic acid.
The compounds of the present invention contain at least one asymmetric center. Additional asymmetric centers may exist on the molecule depending upon the structure of the substituents on the molecule. The compounds may be prepared as a racemic mixture and can be used as such, or may be resolved into all individual steroisomers. In addition to covering the racemic compounds, this invention also covers all individual isomers, enantiomers, diasteromers or mixtures thereof, regardless of whether the structural representations of the compounds indicate such stereochemistry.
The compounds of the present invention may also contain geometric isomers. Thus, the present invention includes all individual isomers and mixtures thereof.
Preferred compounds of Formula I are those in which
A is phenyl or Het;
X is xe2x80x94OCH2xe2x80x94, or a bond;
Y is alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, or piperidine;
Z is S, O, NH or N-alkyl of 1-6 carbon atoms;
R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms;
R4 is hydrogen;
R5 is hydrogen;
R6 is (i) NR7R8; (ii) an amino acid, wherein the nitrogen of amino acid attached to the adjacent thiazolidinone, oxazolidinone, or imidazolidinone ring; (iii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent thiazolidinone, oxazolidinone, or imidazolidinone ring, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; or (iv) NH(C=Q)NR7 R8;
R7 and R8 are each, independently, hydrogen, Het, alkyl of 1-6 carbon atoms, Hetalkyl in which the alkyl moiety has 1-6 carbon atoms, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, cyano, hydroxy, or alkylamino of 1-6 carbon atoms; or R7 and R8 are taken together with the nitrogen to which each is attached to form a saturated, unsaturated, or partially unsaturated 3-8 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from S, O and N, and optionally substituted with R9;
Q is O, S, NH, NCN;
Het is (a) a 6-membered saturated, partially unsaturated, or unsaturated heterocycle containing 1-2 nitrogens, optionally fused to a phenyl ring; (b) a 5-membered saturated, partially saturated, or unsaturated heterocycle containing 1-3 nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl ring; (c) a saturated, partially unsaturated, or unsaturated bicyclic heterocycle containing 1-4 nitrogen, oxygen, or sulfur atoms; (d) carbazole, dibenzofuran, and dibenzothiophene; wherein one or more of the ring carbon atoms of Het as described in (a), (b), or (c) may be a carbonyl moiety, where the ring does not contain a double bond in the position corresponding to that carbon atom; wherein Het may be optionally substituted by R9;
R9 is alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl group;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
a) 4-((2S)-2-hydroxy-3-{1-[4-(2-methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4ylamino}propoxy)-1,3-dihydro-benzoimidazol-2-one;
b) 4-[(2S)-2-hydroxy-3-(1-{4-[2-(2-morpholin-4 -yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;
c) 4-[(2S)-3-(1-{4-[2-(1-benzyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-2-hydroxy-propoxy]-1,3-dihydro-benzoimidazol-2-one;
d) 2-(1-benzyl-piperidin-4-ylamino)-5-(4-{(2S)-4-[2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazol-4-one;
e) N-{5-[2-(1-{4-[2-(1-benzyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1 -hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamide;
f) Nxe2x80x2-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;
g) N-{5-[2-(1-{4-[2-(Nxe2x80x2,Nxe2x80x2-dimethyl-guanidino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl} methanesulfonamide;
h) 3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionic acid ethyl ester;
i) 3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionic acid;
j) 4-((2S)-2-hydroxy-3-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
k) N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
l) 4-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
m) N-[2-hydroxy-5-((1R)-1-hydroxy-2-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
n) N-[2-hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-phenyl]-methanesulfonamide;
o) 8-hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one;
p) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;
q) Nxe2x80x2-[5-(4-{4-[(2S)-2-hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;
r) 4-((2S)-2-hydroxy-3-{1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
s) 4-[(2S)-2-hydroxy-3-(1 -{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;
t) Nxe2x80x2-(5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2-yl)-N,N-dimethyl-guanidine;
u) Nxe2x80x2-[5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;
v) 5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-morpholin-4-yl-thiazol-4-one;
w) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one;
x) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;
y) 5-(4-{4-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one;
z) 2-(3-dimethylamino-propylamino)-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one;
aa) 2-hexylamino-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one;
bb) N-[5-((2R)-2-{1-[4-(2-cyanoamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
cc) (2S)-2-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioic acid;
dd) (2S)-2-[5-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioic acid diethyl ester;
ee) 5-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;
ff) 5-{4-[2-((2S)-2-hydroxy-3-phenoxy-propylamino)-ethoxy]-benzylidene}-2-piperidin-1-yl-thiazol-4-one;
gg) N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; and
hh) 8-hydroxy-5-((2S)-2-hydroxy-3-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one
or a pharmaceutically acceptable salt thereof.
The compounds of this invention were prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
According to one route (Scheme 1), 1,4-dioxa-8-azaspiro[4,5]decane is reacted with 4-fluorobenze 1 in the presence of base such as pyridine or potassium carbonate to afford piperidine derivative 2 (Taylor, E. C., Skotnicki, J. S. Synthesis 1981, 606). This reaction can be carried out in a polar solvent such as anhydrous acetonitrile, acetone, dimethylformamide, or pyridine. Compound 4 is obtained via a Knoevenagel condensation between an appropriate cyclic lactam 3 and the piperidine derivative 2. In this reaction sodium acetate, xcex2-alanine, glycine, pyridine, piperidine, pyrrolidine, sodium methoxide, potassium acetate, sodium carbonate and the like can be used as a base, and an alcohol such as methanol, ethanol, isopropanol, methoxyethanol and the like, dimethylformamide, water, acetic acid and the like can be used as a solvent.
Arylidene compound 6 can be prepared by one of the following synthetic methods (Unangst, P. C., Connor, D. T., Cetenko, W. A., Sorenson, R. J., Kostlan, C. R., Sircar, J. C., Wright, C. D., Schrier, D. J., Dyer, R. D. J. Med. Chem. 1994, 37, 322). One method is a condensation of lactam 4 with amines such as hydroxylamine, N-alkylhydroxyamine, O-alkylhydroxyamine and the like in an alcoholic solvent such as methanol, ethanol, isopropanol and the like at a temperature of 20-100xc2x0 C. The reaction is conveniently conducted in refluxing methanol or ethanol. Alternatively, alkylation of lactam 4 with iodomethane provides methylmercapto compound 5. Reaction of compound 5 with various amines such as methylamine, 4-(2-aminoethyl)morpholine, piperidine and the like in an alcoholic solvent at a temperature of 20-100xc2x0 C. gives the desired intermediate 6. The reaction is also conveniently conducted in refluxing methanol or ethanol.
Many amines are commercially available in the hydrochloride salt or sulfate form. Free amines can be easily obtained by methods well known in the art. For example, treatment of N,N-dimethylguanidine sulfate with a stoichiometric equivalent of potassium t-butoxide in ethanol followed by a quick filtration would produce an alcoholic amine solution. Refluxing of methylmercapto compound 5 with the alcoholic amine solution gives the desired intermediate 6.
Ketal hydrolysis is accomplished in the presence of strong acid such as concentrated hydrochloric acid or 10-30% sulfuric acid. The desired final product 9, wherein A, R1, R2, R3, R4, R5, R6, X and Z are as defined above, is prepared by utilizing reductive amination of piperidiones 7 with appropriate arylethanolamines or aryloxypropanolamines 8. The reductive amination can be carried out, for example, with hydrogen and catalytic palladium, or with sodium borohydride, sodium triacetoxyborohydride and the like in a polar solvent such as methanol, dimethylformamide and the like. The final products can be purified by recrystallization, trituration, preparative thin layer chromatography, flash column chromatography on silica gel, or high pressure liquid chromatography. Purification of intermediates can be achieved in the same manner. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid.
According to another route (Scheme 2), the phenol 10 is subjected to an 0-alkylation with bromoacetaldehyde diethyl ether via phase-transfer catalysis in the presence of base such as potassium carbonate to give the alkylated compound 11. The phase-transfer catalysts could be used in this reaction includes 18-crown-6, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide and the like. The arylidene compound 13 can be prepared, as described in Scheme 1, by substitution of the mercapto compound 12 with amines R6H. In some cases, however, compound 13 could be made directly from the Knoevenagel condensation between intermediate 11, lactams and amines R6H. Ketal hydrolysis followed by reductive amination, as previously described in Scheme 1, furnishes the final product, wherein A, R1, R2, R3, R4, R5, R6, X and Z are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Many of arylethanolamines or aryloxypropanolamines 8 are commercially available or readily prepared by known methods [1. Guy, A., Ferroud, D. C., Garreay, R., Godefroy-Falguieres A. Synthesis, 1992, 821; 2. Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738; 3. Tominaga, M., Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem. Pharm. Bull. 1987, 35, 3699]. In one route (Scheme 3) equimolecular amounts of alcohol 16 and enantiomerically pure (2S)-glycidyl 3-nitrobenzene sulfonate 17 are dissolved in an organic solvent such as acetone or dimethylformamide and treated with a base such as sodium hydride or potassium carbonate for 0.5 to 24 hours at a temperature of 20-100xc2x0 C. to provide oxirane 18. The oxirane 18 is converted to the corresponding amine 20 or 22, wherein A, R1, R2, and R3 are as defined above (provided that in 22 R1, R2, and R3 can not be benzyloxy), by regioselective ring opening of oxirane 18 with either lithium azide in a solvent such as hexamethylphosphoramide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran, or with one equivalent of dibenzylamine followed by ammonium formate/palladium on carbon reduction. The other enantiomer is available through an analogous preparative sequence with the corresponding (2R)-glycidyl 3-nitrobenzene sulfonate. 
One route to the desired arylethanolamines 8 is illustrated in Scheme 4. Methylketones 23 are all available commercially or can be prepared by conventional methods disclosed in the art. Compound 23 can be easily converted to the corresponding xcex1-haloketone 24, wherein halo is chlorine, bromine or iodine, using well known halogenation agents such as chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide and the like. The resultant xcex1-haloketone 24 is then reduced, for example, by sodium borohydride, to give the corresponding racemic alcohol 25. An enantiomerically enriched alcohol 25 may be prepared by asymmetric reduction of xcex1-haloketone 24 with chiral reducing agents such as (+) or (xe2x88x92)-B-chlorodiisopinocampheylborane (DIP-Cl), R or S-Alpine borane, cis-(1R, 2S) or cis (1S, 2R)-oxazaborolidine and the like. The alcohol of intermediate 25 may be protected, for example, as its triethylsilyl ether. In some cases, however, the alcohol protecting group is not required. The halo compound 25 can be easily converted to the corresponding benzylamine 26 by heating to 30-80xc2x0 C. with a large excess of benzylamine neat or as a solution in a polar solvent such as tetrahydrofuran, acetonitrile or methanol for 1 to 24 hours. The protecting group is then removed, in the case of silyl ether, by treatment of 26 with a fluoride agent such as tetrabutylammonium fluoride. Compound 27 is then subjected to catalytic hydrogenation in the presence of ammonium formate/palladium on carbon to give the desired aminoethanol 28, wherein A, R1, R2 and R3 are as defined above. The reduction is conveniently conducted in refluxing methanol in the presence of a large excess of ammonium formate.
Alternatively, the chloride 25 could be converted to the corresponding amine 28 by treatment with a sodium azide/sodium iodide mixture in a polar solvent such as dimethyl sulfoxide, hexamethylphosphoramide and the like followed by catalytic hydrogenation in the presence of a metal catalyst such as palladium, platinum and the like. 
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following standard pharmacological test procedures, which measured the binding selectivity to the xcex21, xcex22, and xcex23 adrenergic receptors. Binding to the receptors was measured in Chinese Hamster ovary (CHO) cells that were transfected with adrenergic receptors. The following briefly summarizes the procedures used and results obtained.
Transfection of CHO cells with xcex21 and xcex22 adrenergic receptors: CHO cells were transfected with human xcex21- or xcex22-adrenergic receptors as described in Tate, K. M., Eur. J. Biochem., 196:357-361 (1991).
Cloning of Human xcex23-AR Genomic DNA: cDNA was constructed by ligating four polymerase chain reaction (PCR) products using the following primers: an ATG-NarI fragment, sense primer 5xe2x80x2-CTTCCCTACCGCCCCACGCGCGATC3xe2x80x2 and anti-sense primer 5xe2x80x2CTGGCGCCCAACGGCCAGTGGCCAGTC3xe2x80x2; a NarI-AccI fragment, 5xe2x80x2TTGGCGCTGATGGCCACTGGCCGTTTG3xe2x80x2 as sense and 5xe2x80x2GCGCGTAGACGMGAGCATCACGAG3xe2x80x2 as anti-sense primer; an Accli-Styl fragment, sense primer 5xe2x80x2CTCGTGATGCTCTTCGTCTCACGCGC3xe2x80x2 and anti-sense primer 5xe2x80x2GTGAAGGTGCCCATGATGAGACCCAAGG3xe2x80x2 and a Styl-TAG fragment, with sense primer 5xe2x80x2CCCTGTGCACCTTGGGTCTCATCATGG3xe2x80x2 and anti-sense primer 5xe2x80x2CCTCTGCCCCGGTTACCTACCC3xe2x80x2. The corresponding primer sequences are described in Mantzoros, C. S., et.al., Diabetes 45: 909-914 (1996). The four fragments are ligated into a pUC 18 plasmid (Gibco-BRL) and sequenced. Full length xcex23 AR clones (402 amino acids) containing the last 6 amino acids of hxcex23-AR are prepared with the xcex23-xcex2ARpcDNA3 from ATTC.
Binding Procedure: Clones expressing receptor levels of 70 to 110 fmoles/mg protein were used in the test procedures. CHO cells were grown in 24-well tissue culture plates in Dulbecco""s Modified Eagle Media with 10% fetal bovine serum, MEM non-essential amino acids, Penicillin-Streptompycin and Geneticin. On the day of test procedure, growth medium was replaced with preincubation media (Dulbecco""s Modified Eagle Media) and incubated for 30 minutes at 37xc2x0 C. Preincubation medium was replaced with 0.2 ml treatment medium containing DMEM media containing 250 xcexcM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test compound dissolved in DMSO. Test compounds were tested over a concentration range of 10xe2x88x929 M to 10xe2x88x925 M for xcex23 cells and 10xe2x88x928 to 10xe2x88x924 M for xcex21 and xcex22 transfected cells. Isoproterenol (10xe2x88x925 M) was used as an internal standard for comparison of activity. Cells were incubated at 37xc2x0 C. on a rocker for 30 min with the xcex23 cells and 15 min for xcex21 and xcex22 cells. Incubation was stopped with the addition of 0.2N HCl and neutralized with 2.5N NaOH. The plates, containing the cells and neutralized media, were stored at xe2x88x9220 degrees celsius until ready to test for cAMP using the SPA test kit (Amersham).
Data Analysis and Results: Data collected from the SPA test procedure were analyzed as per cent of the maximal isoproterenol response at 10xe2x88x925 M. Activity curves were plotted using the SAS statistical and graphics software. EC50 values were generated for each compound and the maximal response (IA) developed for each compound is compared to the maximal response of isoproternol at 10xe2x88x925 M from the following formula:   IA  =            %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      compound              %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      isoproterenol      
Table I shows the xcex23-adronergic receptor EC50 and IA values for the representative compounds of this invention that were evaluated in this standard pharmacological test procedure. These results show that compounds of the present invention have activity at the xcex23-adrenergic receptor. The compounds of this invention had weaker or no activity at xcex21 and/or xcex22-adrenergic receptor.
Based on the results obtained in these standard pharmacological test procedures, representative compounds of this invention have been shown to be selective xcex23 adrenergic receptor agonists and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
As used in accordance with this invention, the term providing an effective amount means either directly administering such a compound of this invention, or administering a prodrug, derivative, or analog which will form an effective amount of the compound of this invention within the body.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of this invention are administered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body. For the poultry and swine raisers, using the method of the present invention yields leaner animals.
Additionally, the compounds of this invention are useful in increasing the lean mass to fat ratio in domestic pets, for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.
The following procedures describe the preparation of intermediates useful in the preparation of compounds of this invention.
(1R)-2-Amino-1-(3-chloro-phenyl)-ethanol:
Lithium azide (7.5 g, 150 mmol) was added to a solution of (1R)-1-(3-chloro-phenyl)oxirane (15.5 g, 100 mmol) in hexamethylphosphoramide (70 mL). After being stirred at room temperature for 16 hours the suspension was poured into ice-water and the mixture was extracted with diethyl ether. The combined extracts were dried over magnesium sulfate and concentrated. The residue was dissolved in 550 mL of tetrahydrofuran/water (10:1) and triphenylphosphine (30 g, 114 mmol) was added. After overnight stirring at room temperature, the solvents were removed and the residue was purified by column chromatography on silica gel using triethylamine-methanol-methylene chloride (1:1:8) as the eluent to give the title compound as a free base.
The title compound was characterized as its hydrochloric salt: The free base from above was then dissolved in diethyl ether and slowly treated with hydrogen chloride gas. The precipitate was collected by filtration to yield 15 g (72%) of the title compound as a white powder; 1H NMR (300 MHz, DMSO-d6) xcex4 2.83 (dd, J=12.8, 9.5 Hz, 1 H), 3.06 (dd, J=12.8, 3.2 Hz, 1 H), 4.80-4.90 (m, 1 H), 6.22 (d, J=4.0 Hz, 1 H), 7.10-7.75 (m, 4 H), 8.08 (brs, 2H); MS (ES) m/z: 171.7, 173.7 (MH+); HRMS Calcd. for C8H10ClNO(MH+): 172.0529. Found: 172.0531.
(2S)-2-Phenoxymethyl-oxirane:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzenesulfonate(25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate concentrated to dryness. The residue was partitioned between methylene chloride and water and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over magnesium sulfate and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) xcex4 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30-3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85-7.00 (m, 3H), 7.25-7.35 (m, 2H); MS (ES) m/z: 151.0 (MH+).
(2S)-1 -Amino-3-phenoxypropan-2-ol:
The title compound was prepared from (2S)-2-phenoxymethyl-oxirane (which was obtained in Intermediate 2) according to the procedure of Intermediate 1 as a white solid; 1H NMR (300 MHz, DMSO-d6) xcex4 2.56 (dd, J=12.8, 6.3 Hz, 1 H), 2.67 (dd, J=12.8, 4.9 Hz, 1 H), 3.65-3.75 (m, 1 H), 3.82 (dd, J=9.8, 6.0 Hz, 1 H), 3.93 (dd, J=9.8, 5.0 Hz, 1 H), 6.85-6.95 (m, 3H), 7.20-7.30 (m, 2H); MS (ES) m/z: 167.7 (MH+); HRMS Calcd. for C9H13NO2(M+): 167.0946. Found: 167.0945.
(2S)-1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol:
The title compound was prepared from (2S)-2-(4-benzyloxy-phenoxymethyl-oxirane (Sher, P. M., et al., EP 0 714 883) according to the procedure of Intermediate 1 as a white solid; 1H NMR (300 MHz, CDCl3) xcex4 2.50-2.70 (m, 2H), 3.33 (brs, 2H), 3.60-3.90 (m, 3H), 5.02 (s, 2 H), 6.90 (d, J=6.7 Hz, 2H), 6.93 (d, J=6.7 Hz, 2H), 7.25-7.50 (m, 5H); MS (ES) m/z: 274.1 (MH+); HRMS Calcd. for C16H19NO3(M+): 273.1365. Found: 273.1347. Anal. Calcd. for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.39; H, 6.80; N, 5.23.
(2S)-1-Amino-3-(4-hydroxy-phenoxy)-propan-2-ol:
A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 4) (0.9 g, 3.3 mmol), 0.2 mL of acetic acid and 10% palladium on carbon (0.3 g) in 70 mL of ethanol was pressurized with 20 psi hydrogen and shaken over 2 hours. The catalyst was then removed by filtering through a short pad of silica gel and the solvent was removed to give the title compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) xcex4 1.86 (s, 1 H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd, J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3 H), 6.67 (d, J=6.6 Hz, 2H), 6.75 (d, J=6.6 Hz, 2 H); MS (ES) m/z: 183.1 (MH+); HRMS Calcd. for C9H13NO3(MH+): 183.0895. Found: 183.0892.
N-[2-Benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide:
N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL of dimethylformamide and treated with dibenzylamine (22.0 g, 110 mmol). The mixture was stirred at room temperature overnight and then the solvent was removed. The residue was purified by silica gel chromatography using 20-50% ethyl acetate/hexanes as eluent to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) xcex4 2.94 (s, 3 H), 3.77 (s, 2 H), 3.82 (s, 2 H), 5.16 (s, 2 H), 6.75 (brs, 1 H), 6.96 (d, J=8.7 Hz, 1 H), 7.20-7.50 (m, 15 H), 7.67 (dd, J=8.7, 2.1 Hz, 1 H), 8.10 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 515.2 (MH+); HRMS Calcd. for C30H30N2O4S(M+): 514.1926. Found: 514.1927.
N-[2-Benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide:
Sodium borohydride (0.37 g, 9.7 mmol) was added in portions to a stirred solution of N-[2-benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide (which was obtained in Intermediate 6) (1.0 g, 1.9 mmol) in 20 mL of methanol/tetrahydrofuran (5:2) at room temperature and the resulting solution was stirred for 2 hours. Methylene chloride was added and the resulting solution was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and the solvents were removed. Recrystallization from methylene chloride/hexanes gave the title compound as a crystalline solid; 1H NMR (300 MHz, CDCl3) xcex4 2.58 (d, J=6.7 Hz, 2 H), 2.86 (s, 2 H), 2.92 (s, 2 H), 3.55 (d, J=13.5 Hz, 2 H), 3.70 (d, J=13.5 Hz, 2 H), 4.11 (s, 1 H), 4.64 (t, J=6.7 Hz, 1 H), 5.10 (s, 2 H), 6.92 (d, J=8.5 Hz, 1 H), 7.00 (dd, J=8.5, 2.0 Hz, 1 H), 7.20-7.50 (m, 16H), 7.89 (brs, 1 H); MS (ES) m/z: 517.1 (MH+); HRMS Calcd. for C30H32N2O4S(M30 ): 516.2083. Found: 516.2074.
N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide:
To a stirred solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (15.05 g, 38 mmol) in dimethyl sulfoxide (150 ml) was added sodium iodide (3.76 g, 376 mmol) and sodium azide (9.48 g, 150 mmol). The mixture was stirred for 5 days under nitrogen atmosphere. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with water and hexanes to give the title compound as a yellow solid (12.85 g, 94%): 1H NMR (300 MHz, CDCl3) xcex4 2.93(s, 3 H), 3.47(d, J=5.4 Hz, 2 H), 4.84(t, J=5.4 Hz, 1 H), 5.11(s, 2 H), 6.80(s, 1 H), 6.99(d, J=8.4 Hz, 1 H), 7.15(dd, J=8.4 Hz, 2.1 Hz, 1 H), 7.26(s, 1 H), 7.30-7.50(m, 5H), 7.53(d, J=2.1 Hz, 1 H); MS (ES) m/z 361.4 ((Mxe2x88x92H)xe2x88x92, 70%).
N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide:
To a stirred suspension of N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Intermediate 7)(1.03 g, 2 mmol) and 10% palladium on carbon (0.4 g) in methanol (100 mL) at room temperature was added anhydrous ammonium formate (1.26 g, 20 mmol) under a nitrogen atmosphere. The resulting mixture was refluxed for 2 hours. After cooling to room temperature the catalyst was removed by filtration through a celite pad and washed with methanol. The filtrate was evaporated under reduced pressure to give the titled compound (Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) xcex4 2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75 (dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H), 6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) mlz: 246.7 (MH+); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672.
N-[5-(2-Amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide:
Method A: A mixture of N-{2-benzyloxy-5-(2-iodo-(1R)-1l-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (8.60 g, 15.3 mmol) and benzylamine (21.4 g, 200 mmol) was heated at 60xc2x0 C. for 24 hours. The reaction mixture was cooled, diluted with hexanes (500 mL), and the residue was washed with diethyl ether. The combined solvents were removed and the residue was purified by silica gel column eluting with 30 to 100% diethyl ether/hexanes. The fractions with molecular weight of 540 were concentrated and re-dissolved in 200 mL of tetrahydrofuran and tetrabutylammonium fluoride (20 mL, 1.0 M solution in tetrahydrofuran) was added. After stirring at room temperature for 4 hours the reaction mixture was then poured into water and extracted with methylene chloride. The organic layers were passed through a short pad of silica gel eluting with 10% methanol/methylene chloride. The solvents were removed and the residue was dissolved in methanol (200 mL). 10% Palladium on carbon (0.6 g) and anhydrous ammonium formate (6.3 g, 100 mmol) were added. The resulting mixture was refluxed under a nitrogen atmosphere for 2 hours. After cooling to room temperature the catalyst was removed by filtration through a celite pad and washed with methanol. The filtrate was evaporated under reduced pressure to give the title compound as an off-white solid; 1H NMR (300 MHz, MeOH-d4) xcex4 2.95 (s, 3 H), 2.99 (dd, J=9.7, 9.2 Hz, 1 H), 3.07 (dd, J=9.7, 3.6 Hz, 1 H), 4.75 (dd, J=9.2, 3.6 Hz, 1 H), 6.90 (d, J=8.3 Hz, 1 H), 7.12 (dd, J=8.3, 2.1 Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7 (MH+); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672. Method B: A mixture of N-[5-((1 R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 8)(12.85 g, 0.037 mol) and 10% palladium on carbon (2.75 g) in ethanol (100 ml) was hydrogenated under 45 psi for two days. The reaction mixture was filtered through celite and concentrated. The title compound was recovered as an off-white solid (6.08 g, 66%).
8-Benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one:
The title compound was prepared from 8-benzyloxy-5-hydroxy-3,4-dihydro-1H-quinolin-2-one (Tominaga, M., Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem. Pharm. Bull. 1987, 35, 3699) according to the procedure of Intermediate 2; 1H NMR (300 MHz, DMSO-d6) xcex4 2.41 (t, J=7.1 Hz, 2 H), 2.69 (dd, J=5.1, 2.7 Hz, 1 H), 2.75-2.86 (m, 4 H), 3.78 (dd, J=11.4, 6.3 Hz, 1 H), 4.23 (dd, J=11.4,2.6 Hz, 1 H), 5.09 (s, 2 H), 6.54 (d, J=9.0 Hz, 2 H), 6.86 (d, J=9.0 Hz, 2 H), 7.25-7.45 (m, 3 H), 7.51 (d, J=8.2 Hz, 2 H), 9.08 (s, 1 H); MS (ES) m/z: 326.0 (MH+); HRMS Calcd. for C19H20NO4(MH+): 326.1392. Found: 326.1343. Anal. Calcd. for C19H19NO4: C, 70.14;H, 5.89; N, 4.30. Found: C, 70.14;H, 5.69; N, 4.20.
5-(3-Amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one:
Dibenzylamine (1.46g, 7.4 mmol) was added to a stirred solution of 8-benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Intermediate 11) (2.0 g, 6.2 mmol) in 100 mL of methanol. After refluxing overnight the mixture was cooled down to room temperature and 10% palladium on carbon (0.5 g) and ammonium formate (3.15 g, 50 mmol) were added. The suspension was refluxed for another hour. After cooling the suspension the reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) xcex4 2.42(t, J=7.1 Hz, 2 H), 2.74 (dd, J=12.8, 8.2 Hz, 1 H), 2.81 (t, J=7.0 Hz, 2 H), 2.95 (dd, J=12.8, 3.4 Hz, 1 H), 3.65-3.95 (m, 3 H), 6.45 (d, J=8.8 Hz, 2 H), 6.62 (d, J=8.8 Hz, 2 H), 8.38 (s, 1 H), 8.77 (brs, 1 H); MS (ES) m/z: 252.9 (MH+); HRMS Calcd. for C12H16N2O4(M+): 252.1188. Found: 252.1199.
N-Benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide:
The title compound was prepared from N-benzyl-N-(2-benzoxy-5-hydro-phenyl)-methanesulfonamide(Kaiser, C.; Jen, T.; Garvey, E.; and Bowen, W. D. J. Med. Chem. 1977, 20, 687) according to the procedure of Intermediate 2 as a white solid; 1H NMR (300 MHz, DMSO-d6) xcex4 2.63(dd, J=5.1, 2.6 Hz, 1 H), 2.80(t, J=4.9 Hz, 1 H), 3.10-3.20(m, 1 H), 3.66(dd, J=11.4, 6.6 Hz, 1 H), 4.16(dd, J=11.4, 2.6 Hz, 1 H), 4.73(brs, 2 H), 5.12(s, 2 H), 6.69 (d, J=3.1 Hz, 1 H), 6.88(dd, J=9.1, 3.1 Hz, 1 H), 7.08 (d, J=9.1 Hz, 1 H), 7.15-7.60(m, 10H); MS (ES) m/z:439.9 (MH+, 100%); HRMS Calcd. for C24 H25NO5S (M+): 439.1454. Found: 439.1457.
N-[5-((2S)-3-Amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide:
The title compound was prepared from N-benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide(which was obtained in Intermediate 13) according to the procedure of Intermediate 12 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) xcex4 2.61 (dd, J=12.7, 6.1 Hz, 1 H), 2.75(dd, J=12.7, 3.5 Hz, 1 H), 2.86(s, 3 H), 3.69-3.90(m, 3 H), 6.55(dd, J=8.7, 3.1 Hz, 1 H), 6.70(d, J=8.7 Hz, 1 H), 6.75 (d, J=3.1 Hz, 1 H); MS (ES) m/z: 276.8 (MH+, 100%); HRMS Calcd. for C10H16N2O5S (M+): 276.0780. Found: 276.0792.
5-[4(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol), rhodanine (2.66 g, 20 mmol), and xcex2-alanine (2.0 g, 22.5 mmol) in 50 mL of acetic acid was refluxed for 2 hours. The solid which was formed on cooling the solution was collected to give the title compound as a red solid (4.8 g, 66%); 1H NMR (300 MHz, CDCl3) xcex4 1.81 (t, J=5.5 Hz, 4 H), 3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H), 7.58 (d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH+); HRMS Calcd. for C17H19N2O3S2(MH+): 363.0837. Found: 363.0852. Anal. Calcd. for C17H18N2O3S2: C, 56.33;H, 5.01; N, 7.73. Found: C, 56.28;H, 4.89; N, 7.73.
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one:
A mixture of 5-[4(1,4-dioxa-8-aza-spiro[4,5]dec-6-yl)-benzylidene]-2-thioxothiazolidin-4-one(which was obtained in Intermediate 15) (1.50 g, 4.14 mmol), N,N-diisopropylethylamine (0.65 g, 5 mmol), iodomethane (1.13 g, 8 mmol) in ethanol (50 mL) was stirred at room temperature overnight. Water (300 mL) was then added and the mixture was stirred for another hour. The solid which was formed was collected and dried to give the title compound as a red solid; 1H NMR (300 MHz, CDCl3) xcex4 1.80 (t, J=5.8 Hz, 4 H), 2.88 (s, 3 H), 3.50 (t, J=5.8 Hz, 4 H), 4.00 (s, 4 H), 6.90 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.0 Hz, 2 H), 7.80 (s, 1 H); MS (ES) m/z: 376.9 (MH+, 100%), 752.9 ((2M+H)+, 5%); HRMS Calcd. for C18H20N2O3S2 (M+): 376.0915. Found: 376.0888. Anal. Calcd. for C18H20N2O3S2: C, 57.42;H, 5.35; N, 7.44. Found: C, 57.34; H, 5.18; N, 7.34.
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2 -methylamino-thiazo-4-one:
A mixture of 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) (0.56 g, 1.5 mmol) and methylamine (7.5 mL, 2.0 M solution in tetrahydrofuran) in ethanol (100 mL) was refluxed overnight. After cooling to room temperature hexanes (70 mL) was added and the solid which was formed was collected to give the title compound as a yellowish solid (olefinic cis/trans mixture, ratio 3 to 1); 1H NMR (300 MHz, CDCl3) xcex4 1.75-1.85 (m, 4 H), 3.19 (s, 3 H), 3.40-3.50 (m, 4 H), 4.00(s, 4 H), 6.98 (d, J=9.0 Hz, 2 H), 7.46 (d, J=9.0 Hz, 2 H), 7.71 (s, 1 H); MS (ES) m/z: 359.9 (MH+, 100%), 719.0 ((2M+H)+, 10%); HRMS Calcd. for C18H21N3O3S (M+): 359.1304. Found: 359.1307.
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylamino-thiazo-4-one(which was obtained in Intermediate 17) (0.25 g, 0.7 mmol) was treated with concentrated hydrochloric acid (18 mL) at room temperature. After 30 minutes the solution was neutralized with xe2x88x9228% ammonium hydroxide and the precipitate was collected by filtration, and dried to give the title compound as a yellowish solid (0.20 g, 91%, olefinic cis/trans mixture, ratio 5 to 1); 1H NMR (300 MHz, DMSO-d6) xcex4 2.43 (t, J=5.9 Hz, 4 H), 3.05 (s, 3 H), 3.73 (t, J=5.9 Hz, 4 H), 7.13 (d, J=7.3 Hz, 2 H), 7.46 (d, J=7.3 Hz, 2 H), 7.50 (s, 1 H), 9.41 (brs, 1 H); MS (ES) m/z: 315.8 (MH+, 100%), 631.0 ((2M+H)+, 10%); HRMS Calcd. for C16H17N3O2S (M+): 315.1041. Found: 315.1057.
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-(2-morpholin-4-yl-ethylamino)-thiazo-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and 4-(2-aminoethyl) morpholine according to the procedure of Intermediate 17 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.68 (t, J=5.5 Hz, 4 H), 2.35-2.55 (m, 6 H), 3.44 (t, J=5.5 Hz, 4 H), 3.55-3.65 (m, 6 H), 3.92(s, 4 H), 7.07 (d, J=8.9 Hz, 2 H), 7.40 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H), 9.43 (brs, 1 H); MS (ES) m/z: 229.9 ((M+2H)2+, 40%), 458.9 (MH+, 100%), 917.2 ((2M+H)+, 3%); HRMS Calcd. for C23H30N4O4S (M+): 458.1988. Found: 458.1979.
1-{4-[2-(2-Morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-(2-morpholin-4-yl-ethylamino)-thiazo-4-one(which was obtained in Intermediate 19) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 2.30-2.55(m, 10H), 3.50-3.70 (m, 6 H), 3.74 (t, J=5.9 Hz, 4 H), 7.11 (d, J=8.7 Hz, 2 H), 7.45 (d, J=8.7 Hz, 2 H), 7.50 (s, 1 H), 9.46 (brs, 1 H); MS (ES) m/z: 414.9 (MH+, 100%), 829.1 ((2M+H)+, 2%); HRMS Calcd. for C21H26N4O3S (M+): 414.1726. Found: 414.1734.
1-{4-[2-(1-Benzyl-piperdin-4-ylamino)4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and 4-amino-1-benzylpiperidine according to the procedures of Intermediate 17 and Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.50-4.00(m, 9H), 2.43 (t, J=5.9 Hz, 4 H), 3.33 (s, 2 H), 3.74 (t, J=5.9 Hz, 4 H), 7.12 (d, J=8.7 Hz, 2 H), 7.20-7.50 (m, 5H), 7.44 (d, J=8.7 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 475.0 (MH+, 100%), 949.3 ((2M+H)+, 2%); HRMS Calcd. for C27H30N4O2S (M+): 474.2089. Found: 474.2085.
3-[5-(4-Oxo-piperidin-1-yl)-benzylidene-4-oxo-4,5-dihydrothiazol-2-ylamino]-propionic acid ethyl ester
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and xcex2-alanine alanine ethyl ester according to the procedures of Intermediate 17 and Intermediate 18 as a yellowish solid (one major isomer); MS (ES) m/z: 402.2 (MH+, 100%).
N,N-Dimethyl-Nxe2x80x2-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and 1,1-dimethyiguanidine sulfate according to the procedures of Intermediate 17 and Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 2.49 (t, J=6.0 Hz, 4 H), 2.90-3.20 (m, 6 H), 3.73 (t, J=6.0 Hz, 4 H), 7.10 (d, J=9.0 Hz, 2 H), 7.47 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 372.0 (MH+); HRMS Calcd. for C18H22N5O2S (MH+): 372.1416. Found: 372.1404.
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-hydroxyamino-thiazol-4-one:
A solution of hydroxyamine hydrochloride (2.09 g, 30 mmol) in methanol (50 mL) was treated in portions with potassium tert-butoxide (3.25 g, 29 mmol). The mixture was stirred for 30 minutes and then rapidly filtered into a suspension of 5-[4(1,4-dioxa-8-aza-spiro[4,5]dec-6-yl)-benzylidene]-2-thioxothiazolidin-4-one (which was obtained in Intermediate 15)(1.81 g, 5 mmol) in methanol (200 mL). The reaction mixture was refluxed overnight. Upon cooling the precipitated solid was collected to give the title compound as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.68 (t, J=5.5 Hz, 4 H), 3.16 (d, J=5.2 Hz, 1 H), 3.44 (t, J=5.5 Hz, 4 H), 3.92 (s, 4 H), 7.07 (d, J=8.7 Hz, 2 H), 7.40 (d, J=8.7 Hz, 2 H), 7.45 (s, 1 H); MS (ES) m/z: 361.8 (MH+); HRMS Calcd. for C17H19N3O4S (M+): 361.1096. Found: 361.1113.
1-[4-(4-Oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and piperidine according to the procedures of Intermediate 17 and Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.50-1.75(m, 6 H), 2.43 (t, J=5.9 Hz, 4 H), 3.55-3.70 (m, 2 H), 3.74 (t, J=5.9 Hz, 4 H), 3.80-3.95 (m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 370.0 (MH+, 100%), 739.1 ((2M+H)+, 5%); HRMS Calcd. for C20H23N3O2S (M+): 369.1511. Found: 369.1518.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-morpholin-4-yl-thiazol-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and morpholine according to the procedure of Intermediate 17 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.68 (brt, J=5.6 Hz, 4 H), 3.45 (brt, J=5.6 Hz, 4 H), 3.60-3.70(m, 2 H), 3.70-3.80(m, 4 H), 3.90-3.92(m, 2 H), 3.92(s, 4 H), 7.05 (d, J=7.6 Hz, 2 H), 7.49 (d, J=7.6 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 416.0 (MH+, 100%); HRMS Calcd. for C21H25N3O4S (M+): 415.1565. Found: 415.1570.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and 4-methylpiperazine according to the procedure of Intermediate 17 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.68 (brt, J=5.6 Hz, 4 H), 2.22(s, 3 H), 2.40-2.50(m, 4 H), 3.41 (brt, J=5.6 Hz, 4 H), 3.60-3.65(m, 2 H), 3.90-4.05(m, 2 H), 4.05(s, 4 H), 7.05 (d, J=8.7 Hz, 2 H), 7.46 (d, J=8.7 Hz, 2 H), 7.53 (s, 1 H); MS (ES) m/z: 429.0 (MH+, 100%); HRMS Calcd. for C22H28N4O3S (M+): 428.1882. Found: 428.1869.
1-[4-(2-Morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-morpholin-4-yl-thiazol-4-one(which was obtained in Intermediate 26) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 2.44 (t, J=6.0 Hz, 4 H), 3.60-3.80(m, 10H), 3.85-3.95(m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H), 7.57 (s, 1 H); MS (ES) m/z: 372.0 (MH+, 100%); HRMS Calcd. for C19H21N3O3S (M+): 371.1303. Found: 371.1310.
1-{4-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one(which was obtained in Intermediate 27) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 2.24(s, 3 H), 2.40-2.60(m, 8H), 3.60-3.70(m, 2 H), 3.74(t, J=6.0 Hz, 4 H), 3.85-3.95(m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H), 7.55 (s, 1 H); MS (ES) m/z: 385.0 (MH+, 100%); HRMS Calcd. for C20H24N4O2S (M+): 384.1620. Found: 384.1616.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-hexylamino-thiazol-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and hexylamine according to the procedure of Intermediate 17 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 0.87 (t, J=6.6 Hz, 3 H), 1.20-1.40(m, 6 H), 1.50-1.60(m, 2 H), 1.66 (brt, J=5.6 Hz, 4 H), 3.40-3.60(m, 6 H), 3.92(s, 4 H), 7.06 (d, J=8.9 Hz, 2 H), 7.39 (d, J=8.9 Hz, 2 H), 7.48 (s, 1 H), 9.50(brs, 1 H); MS (ES) m/z: 430.0 (MH+, 100%); HRMS Calcd. for C23H31N3O3S (M+): 429.2086. Found: 429.2081.
Intermediate 31
2-(3-Dimethylamino-propylamino)-5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazol-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and 3-dimethylaminopropylamine according to the procedure of Intermediate 17 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.60-1.70(m, 6 H), 2.10(s, 6 H), 2.25 (t, J =7.0 Hz, 2 H), 3.30-3.50(m, 6 H), 3.85(s, 4 H), 7.07 (d, J=9.0 Hz, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48 (s, 1 H), 9.50(brs, 1 H); MS (ES) m/z: 431.1 (MH+, 100%); HRMS Calcd. for C22H30N4O3S (M+): 430.2038. Found: 430.2040.
1-[4-(2-Hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-hexylamino-thiazol-4-one(which was obtained in Intermediate 30) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 0.87(t, J=6.5 Hz, 3 H), 1.20-1.40(m, 6 H), 1.50-1.75(m, 2 H), 2.43(t, J=5.9 Hz, 4 H), 3.40-3.55(m, 2 H), 3.74 (t, J=5.9 Hz, 4 H), 7.12 (d, J=8.9 Hz, 2 H), 7.44 (d, J=8.9 Hz, 2 H), 7.50 (s, 1 H), 9.47(t, J=5.3 Hz, 1 H); MS (ES) m/z: 386.0 (MH+, 100%); HRMS Calcd. for C21H27N3O2S (M+): 385.1824. Found: 385.1809.
1-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:
The title compound was prepared from 2-(3-dimethylamino-propylamino)-5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazol-4-one(which was obtained in Intermediate 31) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.60-1.80(m, 2 H), 2.24(s, 6 H), 2.30-2.45(m, 6 H), 3.51(t, J=6.9 Hz, 2 H), 3.74 (t, J=5.9 Hz, 4 H), 7.12 (d, J=9.0 Hz, 2 H), 7.44 (d, J=9.0 Hz, 2 H), 7.53 (s, 1 H); MS (ES) m/z: 387.0 (MH+, 100%); HRMS Calcd. for C20H26N4O2S (M+): 386.1776. Found: 386.1768.
(2S)-2-{5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one (which was obtained in Intermediate 16) and diethyl L-glutamate hydrochloride according to the procedure of Intermediate 24 as a yellowish solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.17(t, J=7.1 Hz, 3 H), 1.21(t, J=7.1 Hz, 3 H), 1.68(brt, J=5.6 Hz, 4 H), 3.45(brt, J=5.6 Hz, 4 H), 3.91(s, 4 H), 4.05(q, J=7.1 Hz, 2 H), 4.15(q, J=7.1 Hz, 2 H), 4.60-4.70(m, 1 H), 7.07 (d, J=9.0 Hz, 2 H), 7.42 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z:532.0 (MH+, 100%); HRMS Calcd. for C26H33N3O7S (MH+): 532.2117. Found: 532.2115.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl-cyanamide:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and cyanamide according to the procedure of Intermediate 24 as a red solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 1.68(brt, J=5.6 Hz, 4 H), 3.45(brt, J=5.6 Hz, 4 H), 3.92(s, 4 H), 7.05 (d, J=9.0 Hz, 2 H), 7.33(s, 1 H), 7.39 (d, J=9.0 Hz, 2 H); MS (ES) m/z:370.9 (MH+, 100%); HRMS Calcd. for C18H19N4O3S (MH+): 371.1172. Found: 371.1172.
4-Oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl-cyanamide:
The title compound was prepared from 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]4-oxo-4,5-dihydro-thiazol-2-yl-cyanamide(which was obtained in Intermediate 35) according to the procedure of Intermediate 18 as a red solid (one major isomer); 1H NMR (300 MHz, DMSO-d6) xcex4 2.43(t, J=6.0 Hz, 4 H), 3.76(t, J=6.0 Hz, 4 H), 7.12 (d, J=9.0 Hz, 2 H), 7.36(s, 1 H), 7.47 (d, J=9.0 Hz, 2 H); MS (ES) m/z:326.7 (MH+, 100%); HRMS Calcd. for C16H15N4O2S (MH+): 327.0910. Found: 327.0909.
5-[4-(2,2-Diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one:
Under nitrogen, a mixture of 4-hydroxybenzaldehyde (1.71 g, 14 mmol), bromoacetaldehyde diethyl acetate (37.4 g, 190 mmol), tetrabutylammonium bromide (0.61 g, 1.9 mmol) and potassium carbonate (26.1 g, 190 mmol) in 100 mL of toluene was refluxed for 2.5 days. After cooling the mixture was dissolved in water and extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexanes/ethyl acetate) to give 4-(2,2-diethoxyethoxy) benzaldehyde as a colorless oil (2.60 g, 79%). The title compound was prepared from 4-(2,2-diethoxyethoxy) benzaldehyde and rhodanine according to the procedure of Intermediate 15 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) xcex4 1.14(t, J=7.1 Hz, 6 H), 3.50-3.80 (m, 4 H), 4.04(d, J=5.0 Hz, 2 H), 4.05-4.30(m, 2 H), 6.06 (t, J=5.0 Hz, 1 H), 7.14 (d, J=9.0 Hz, 2 H), 7.60 (d, J=9.0 Hz, 2 H), 7.63(s, 1 H); MS (ES) m/z:351.7 ((Mxe2x88x92H)xe2x88x92, 100%); HRMS Calcd. for C16H20NO4S2 (MH+): 353.0775. Found: 353.0757.
5-[4-(2,2-Diethoxy-ethoxy)-benzylidene]-2-piperidin-1-yl-thiazol-4-one:
A mixture of 5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (which was obtained in Intermediate 37)(1.19 g, 5 mmol), rhodanine (0.67 g, 5 mmol) and piperidine (1.72 g, 20.2 mmol) in ethanol (50 mL) was refluxed for 2 hours. After cooling to room temperature hexanes (70 mL) were added and the solid which was formed was collected to give the title compound as a yellowish solid (1.4 g, 69%); 1H NMR (300 MHz, DMSO-d6) xcex4 1.14(t, J =7.1 Hz, 6 H), 1.55-1.75(m, 6 H), 3.40-3.80 (m, 6 H), 3.85-3.95(m, 2 H), 4.02(d, J=5.2 Hz, 2 H), 4.82 (t, J=5.2 Hz, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 7.57 (d, J=7.6 Hz, 2 H), 7.58(s, 1 H); MS (ES) m/z: 404.9 (MH+, 100%); HRMS Calcd. for C21H28N2O4S (M+): 404.1770. Found: 404.1780.
4-(4-Oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-acetaldehyde hydrate:
The title compound was prepared from 5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-piperidin-1-yl-thiazol-4-one(which was obtained in Intermediate 38) according to the procedure of Intermediate 18 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) xcex4 1.50-1.75(m, 6 H), 3.55-3.70 (m, 2 H), 3.80-3.95(m, 4 H), 5.05-5.65(m, 1 H), 6.12(d, J=6.6 Hz, 2 H), 7.07 (d, J=9.0 Hz, 2 H), 7.57 (d, J=9.0 Hz, 2 H), 7.58(s, 1 H); MS (ES) m/z: 348.9 ((M+H2O+H)+, 100%); HRMS Calcd. for C17H18N2O3S (M+): 330.1038. Found: 330.1040.
5-[4-(4-Oxo-pyridin-1-yl)-benzylidene]-2-hydroxyamino-thiazo-4-one
The title compound was prepared from 5-[4-(1,4-ioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-hydroxyamino-thiazol-4-one(which was obtained in Intermediate 24) according to the procedure of Intermediate 18 as a yellowish solid (one major isomer); MS (ES) m/z: 318.2 (MH+, 100%).